# Revealing the complexity of dis-inhibitory circuitries

> **NIH NIH R21** · TRUSTEES OF INDIANA UNIVERSITY · 2024 · $435,875

## Abstract

PROJECT SUMMARY
Salient signals, like aversive stimulation and reward, should be faithfully detected, and processed by the
nervous system to generate an adaptive action. One of the universal circuit mechanisms linked to salient signal
processing in cortical operation is the activation of dis-inhibitory neurons by subcortical afferents. Aversive
signals and reward delivery profoundly excite cortical GABAergic interneurons expressing vasoactive intestinal
polypeptide (VIP), which selectively inhibit other GABAergic interneurons, leading to the dis-inhibition of
cortical pyramidal cells. In this project, we propose to reveal the functional diversity of VIP interneurons in a
cortical structure. The central idea of our project rests on our earlier anatomical findings that distinct groups of
VIP interneurons innervate different types of GABAergic interneurons, observations that prompted us to
suggest a heterogeneity in their activity during various cortical processes. However, recent imaging studies
reported rather similar activity of VIP interneurons following aversive and appetitive stimuli. In contrast to these
in vivo imaging data, our preliminary experiments obtained in a frontal cortical area of anesthetized mice have
revealed a considerable heterogeneity in VIP interneuron spiking upon delivery of foot shocks. Building on
these preliminary results, our goal is to determine the functional complexity of cortical VIP interneurons,
including their connectivity and operation in awake mice. To achieve these aims, we will combine viral
techniques, neuroanatomical methods, in vivo and in vitro electrophysiology with optogenetics in three different
genetically modified mouse lines. The results of this project will uncover the heterogeneity of spike responses
generated by genetically defined dis-inhibitory VIP interneurons upon salient signal delivery and their
downstream effects on postsynaptic partners within the local microcircuits. Our project will reveal the
complexity of dis-inhibitory circuit motifs in cortical networks, which may be a general phenomenon in a cortex-
wide manner. In addition, our results will help form novel concepts underlying the pathological operation of
cortical circuits linked to deficits in attention and salient signal detection that typifies many malfunctional
cognitive processes, including those observed in schizophrenia, autism, and attention deficit.

## Key facts

- **NIH application ID:** 11039382
- **Project number:** 1R21NS140988-01
- **Recipient organization:** TRUSTEES OF INDIANA UNIVERSITY
- **Principal Investigator:** Norbert Hajos
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $435,875
- **Award type:** 1
- **Project period:** 2024-09-20 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11039382

## Citation

> US National Institutes of Health, RePORTER application 11039382, Revealing the complexity of dis-inhibitory circuitries (1R21NS140988-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11039382. Licensed CC0.

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